The calcium-sensing receptor CaSR mediates airway contraction in a house dust mite model of allergic airway disease

Abstract

Introduction: The CaSR detects changes in extracellular calcium to maintain homeostasis (Leach, Trends Pharmacol Sci, 2015). This putative drug target is upregulated in asthma, and allosteric agonists for CaSR, such as the polyamine spermine, induce bronchoconstriction. Further, negative allosteric modulators (calcilytics) reduce airway inflammation, remodelling and AHR in a chronic mouse asthma model (Yarova, Sci Transl Med, 2015; Lee, Mol Immunol, 2018). Aim: To investigate CaSR by comparing airway reactivity to the polycation, spermine, with methacholine (MCh), using precision cut lung slices (PCLS) from an acute house dust mite (HDM) mouse model. Methods: PCLS were prepared from female Balb/C mice sensitized and challenged with 100 μg HDM i.n. on Days 0 and 14 to visualise intrapulmonary airways (100-300 μm diam) and contraction to spermine and MCh. Lung sections were scored for peribronchial inflammation (0 - none; 4 - severe). Results: In PCLS from saline mice, contraction to spermine occurred with lower potency and maximum than MCh (% reduction in area: 3 mM spermine 31 ± 5%; 3 µM MCh 60 ± 8%; n=3), and was abolished by the calcilytic NPS2143. After HDM, moderate cell aggregates were evident around the airways (inflammation: saline 0.5 ± 0.5; HDM 2.9 ± 0.2; n=6, P Conclusion: Spermine elicits CaSR-dependent contraction of mouse airways. Our short-term HDM model induced airway inflammation, but not in vitro AHR to MCh or increased contraction via CaSR. Studies in chronic HDM models may inform whether the CaSR contributes to increased airway contraction in asthma.